Dr. Flaherty has been the principal investigator of the first combination targeted therapy trial to build on single agent BRAF inhibition in which a selective MEK inhibitor is combined with this agent. In addition to being the academic architect of these clinical trial protocols, Dr. Flaherty and colleagues at DF/HCC have accrued the largest number of patients to these trials. As a consequence, our center not only has the longest clinical experience with these agents, but also an increasingly large repository of archival tumor specimens and fresh tumor biopsies obtained before and during treatment, as well as at the time of clinical progression. This Core will continue to collect tumor biopsies prior to and during treatment with BRAF inhibitors, and then identify and isolate cellular constituents of the tumor microenvironment including immune subpopulations, endothelial cells, pericytes, and fibroblasts. We will also genetically characterize tumor cells for previously described oncogene and tumor suppressor gene alterations including point mutations and copy number. Our group is uniquely poised to direct our clinical and research infrastructure to studying the problem of resistance to BRAF targeted therapy.